This is a competitive renewal application that builds on the achievements of a previously NIH funded project. The longterm goal of that study was and is to develop an optical tomographic imaging modality to assist in the diagnosis, chracterization, and monitoring of joint diseases. Towards that goal we have successfully implemented and tested image reconstruction schemes and instrumentation for optical tomographic imaging of finger joints. Using theses codes and instrumentation we have performed clinical pilot studies with 30 patients to explore the feasibility of diagnosing rheumatoid arthritis (RA). We showed that optically derived classifiers can be found that can distinguish between affected and non-affected joints and that correlate well with ultrasound findings and clinical examination. The initial hypothesis that changes in the synovial fluid provide optical contrast appeared to be true, however, the clinical results suggest a more complex scenario as initially expected. Based on our studies we now believe that three main processes (effusion, erosion, and hypertrophy of the synovial membrane (synovitis)) that accompany RA can be distinguished by optical tomography (OT). Doing so without contrast agents, OT promises to provide a convenient, non-invasive, and economical imaging adjunct to existing modalities. However, to be able to better distinguish between these different symptoms and detect smallest changes in optical properties as early as possible, one needs to improve the spatial resolution and enhance differentiation between optical absorption and scattering effects. The main hypothesis of this renewal application is that this can be achieved by moving from a steady-state imaging system to a frequency-domain imaging device. In detail, we propose the following three specific aims: (1) Develop a model-based iterative image reconstruction code that uses the three-dimensional frequency-domain equation of radiative transfer as an accurate model of light propagation in tissue. Such a code does currently not exist but is essential for accurate imaging in small geometries that include void-like spaces with low scattering and absorption coefficients. (2) Assemble and optimize a frequency-domain charge-coupled-device (CCD) camera system that allows for the acquisition of a larger number of data points in a shorter period of time. By being ergonometrically designed the system will be patient friendly and together with faster data acquisition minimizes movement artifacts. (3) Perform clinical studies that will allow quantifying the sensitivity and specificity of optical tomographic imaging with respect to detecting the three major aspects (effusion, erosion, and synovitis) of RA. Besides gaining fundamental knowledge on contrast mechanisms in OT joint imaging, we will specifically focus on detection of symptoms characteristic for early RA. The performance of the new code and improved instrumentation will be compared with the currently existing system. The ultimate goal of this proposal is to lay the groundwork for a clinical viable joint imager that can be used in a phase II clinical trial in i subsequent studies.